ABSTRACT
Congenital adrenal hyperplasia, one of the most frequent autosome recessive disorders, is caused by defects in steroidogenic enzymes involved in the cortisol biosynthesis. Approximately 95% of the cases are caused by abnormal function of the 21-hydroxylase enzyme. This deficiency leads to androgen excess, consequently, to virilization and rapid somatic growth with accelerated skeletal maturation. Mutations in CYP21A2 are responsible for different forms of 21-hydroxylase deficiency. Mild impairment in the enzymatic activity causes the non-classic or late-onset congenital adrenal hyperplasia that is observed with a prevalence of 1 in 1000 subjects in different populations. The present paper describes a de novo mutation that occurred in the paternal meiosis. The child, who was conceived by in vitro fertilization, presented with precocious puberty and diagnosed with non-classical 21-hydroxylase deficiency. DNA sequencing showed the compound heterozygosis for a de novo CYP21A1P/A2 chimeric gene and the p.Val281Leu mutation inherited from her mother, who was heterozygous for the mutation. The chimeric gene showed pseudogene-derived sequence from 5'-end to intron 3 and CYP21A2 sequences from intron 3 to 3'-end of the gene. Sequencing analysis of the father did not show any mutation. The multiplex ligation-dependent probe amplification (MLPA) assay did not indicate loss of DNA discarding gene deletion but confirmed the chimeric gene. In addition, supernumerary copies of CYP21A1P were observed for both parents and for the affect child. Since paternity has been confirmed, those results suggest that a de novo large gene conversion in the paternal meiosis could have occurred by misalignment of alleles bearing different copy numbers of genes in CYP21 locus.
ABSTRACT
OBJECTIVE: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is characterized by high androgen levels, ambiguous genitalia or premature pubarche, increased height velocity and skeletal maturation. Considering the possibility of changes in the IGF system components depending on the state of clinical control, the objective of the present study was to analyse serum IGF-I, IGF-II and IGFBP levels in children with 21-OHD under two states of clinical control. PATIENTS AND DESIGN: We studied 12 prepubertal children with 21-OHD CAH aged 4.0 +/- 0.7 years. They were classified as good (GC) or poor control (PC) based on growth rate, signs of adrenal insufficiency or Cushing syndrome, progression of sexual characteristics and serum androgens levels. Blood samples were obtained from each patient in two different states of clinical control (GC and PC) for biochemical measurements. MEASUREMENTS: IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 were determined by immunoassays. IGFBPs were also analysed by Western ligand blotting (WLB). RESULTS: Levels of IGF-I (P = 0.03) and IGFBP-3 (P = 0.01) were higher in GC than in PC while IGFBP-1 (P = 0.004) concentrations were lower in GC patients. A trend towards higher levels of IGF-II (P = 0.08) and lower levels of IGFBP-2 (P = 0.08) was observed in GC children. Increased IGFBP-4 band intensity was observed in GC children (P = 0.03). CONCLUSION: Higher levels of IGF-I, IGFBP-3 and IGFBP-4, but lower levels of IGFBP-1, were associated with better control in children with 21-OHD CAH. These findings are different from those observed in children with other causes of increasing androgens levels and are likely to be related to the insufficient glucocorticoid status.
